We completed the first phase of a study to evaluate the quality of the DNA in the HAAS samples that was extracted in 1994 for Apolipoprotein E genotyping. The conslusion was that the DNA quality could only be used reliably for very robust PCR analyses. Therefore, as a first step in the project we will extract new DNA from the remaining buffy coat in a nested case control study that includes all cases of dementia identified in exams 4 and 5, cases of mild cognitive impairment (defined as a drop in CASI score of >4pts per year), a random set of controls frequency matched in 5-year strata to the cases. In the second stage, we will conduct association studies of polymorphisms in relation to the risk for dementia. In line with the research objective of investigating the association of blood pressure to the risk of dementia, our first candidate gene to investigate is the Angiotensin Converting Enzyme (ACE) polymorphism. In the HAAS cohort, we found an association of high blood pressure to an increased risk for cognitive impairment, clinical AD (2) and neuropathologic markers of AD. We found that men never treated with antihypertensives were at the greatest risk for cognitive impairment and dementia. The data were also suggestive of increased risk for AD (clinical and neuropathologic markers) among those with low blood pressure. The ACE polymorphism has been implicated as a susceptibility gene for AD. Dr. L.Farrer has recently found an association between the D allele of the ACE polymorphism and an increased risk of AD in two cohorts, one from Russia and one from North America.